Thymidylate synthase and thymidine phosphorylase mRNA expression in primary lesions using laser capture microdissection is useful for prediction of the efficacy of FOLFOX treatment in colorectal cancer patients with liver metastasis

Abstract

Abstract. Chemotherapy with FOLFOX, which is a combination of 5-fluorouracil (5-FU)/leucovorin (LV) and oxaliplatin, has been used worldwide for the treatment of metastatic colorectal cancer patients. The aim of this study was to examine the candidates for predictors of the efficacy of the FOLFOX treatment regimen in colorectal cancer patients with liver metastasis, using formalin-fixed paraffin-embedded specimens. We investigated the mRNA levels of thymidylate synthase (TS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT) and excision repair cross-complementing 1 (ERCC1) in 70 primary lesions and 30 liver metastatic lesions of colorectal cancer patients, using laser capture microdissection and real-time PCR methods. We then analyzed the correlation between their expression in primary lesions and those in corresponding liver metastatic lesions (n=30) and the relationship between their expression in the primary lesions and the efficacy of mFOLFOX6 in 45 colorectal cancer patients with unresectable liver metastasis. The gene expression in primary lesions positively correlated with those in corresponding liver metastatic lesions. The profiles of gene expression of primary lesions strongly correlated with those of synchronous liver metastatic lesions compared to that of metachronous liver metastatic lesions. TS and TP mRNA levels in the patients with complete response, partial response or stable disease (n=34) were significantly lower compared to those in the patients with progressive disease (n=11) (p=0.017 and p=0.04, respectively). Our results indicated that TS and TP mRNA expression profiles in primary lesions are sufficient to estimate the mRNA expression profiles in synchronous liver metastatic lesions compared to metachronous liver metastatic lesions. Additionally, these profiles may be useful predictors in the identification of eligible colorectal cancer patients with liver metastasis for FOLFOX treatment.

Evaluation of 5‐Fluorouracil Metabolic Enzymes as Predictors of Response to Adjuvant Chemotherapy Outcomes in Patients with Stage II/III Colorectal Cancer: A Decision‐Curve Analysis

“…A positive correlation between TS and TP mRNA expression has also been reported by van Triest et al [30]. Therefore, the results of our study are considered to be reliable and consistent with those reported in previous studies [17,31]. Although many previous studies have investigated the expression of 5-FU metabolic enzymes to assess whether they are predictive biomarkers of 5-FU response, the impact of these enzymes as biomarkers is still weak.…”

Polymorphisms of GSTP1, ERCC2 and TS-3′UTR are associated with the clinical outcome of mFOLFOX6 in colorectal cancer patients

“…Treatment with FOLFIRI was also administered as second-line chemotherapy to ~70% of patients receiving mFOLFOX6 treatment, and hence, the patients with increased survival rates were exposed to 5-FU for a long time. Numerous studies have indicated that MCRC patients with lower TS expression have a favorable outcome following 5-FU-based chemotherapy compared with patients with high TS expression (10,28). A previous study revealed that TS mRNA expression in rectal cancer patients with the TS -3′-UTR −6/−6 and −6/+6 genotypes was significantly lower compared with patients with the TS -3′-UTR +6/+6 genotype, resulting in a favorable outcome following neoadjuvant 5-FU-based chemoradiation (29).…”

“…Gene expression analysis, associated with the metabolism of 5-FU and oxaliplatin, has been intensively studied (6–9). It has been reported that thymidylate synthase ( TS) and thymidine phosphorylase ( TP ) mRNA expression levels are useful markers for predicting the efficacy of FOLFOX treatment in CRC patients with liver metastasis (10). In addition, advances in molecular biology indicate that a number of drug metabolism genes have polymorphisms that alter levels of expression.…”

Safety of implanting sustained-release 5-fluorouracil into hepatic cross-section and omentum majus after primary liver cancer resection

“…Moreover, after the implantation, released 5-FU plays relevant functions after diffusing into extracellular tissue fluid; the extremely small amount of the drug entering into the blood through the capillary wall results in low peak concentration, which avoids toxic and side effects. [10][11][12][13] We found that sustained-release 5-FU could inhibit liver cancer and rapid proliferation of residual cancer cells after surgical resection, and sustained-release 5-FU conforming to the concept and requirement of regional chemotherapy and interstitial chemotherapy was operable and valuable.…”